Studies on the mechanism of action of 2-formyl-4-pyrrolidinopyridine: Isolation and characterization of a reactive intermediate

Article abstract of DOI:10.1021/jo982281n

This paper describes the mechanism of action of 2-formyl-4- pyrrolidinopyridine (FPP, 1a) which is a catalyst for the hydroxyl-directed methanolysis of α-hydroxy esters. This species was initially designed to act as a nucleophilic catalyst; however, we have ruled out a nucleophilic mechanism by examining the activity of 6-substituted-FPP derivatives. These compounds are more hindered in the vicinity of the pyridine nitrogen than FPP itself but are also more active catalysts. Furthermore, the presence of p- nitrophenol, a mild acid, was found to accelerate the catalytic reaction. These results are inconsistent with a nucleophilic catalysis mechanism. We provide evidence that the reaction instead proceeds via dioxolanone intermediate 10. Dioxolanone 10 can be obtained by treating either the p- nitrophenyl ester or the pentafluorophenyl ester of glycolic acid with FPP in chloroform in the absence of methanol. It has been isolated, characterized, and shown to be kinetically competent when subjected to the conditions of the catalytic reaction.

Full text of DOI:10.1021/jo982281n

4652
J . Org. Chem. 1999, 64, 4652-4664
Stu d ies on th e Mech a n ism of Action of
2-F or m yl-4-p yr r olid in op yr id in e: Isola tion a n d Ch a r a cter iza tion of
a Rea ctive In ter m ed ia te
Tarek Sammakia* and T. Brian Hurley
Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado 80309-0215
Received November 17, 1998 (Revised Manuscript Received March 23, 1999)
This paper describes the mechanism of action of 2-formyl-4-pyrrolidinopyridine (FPP, 1a ) which is
a catalyst for the hydroxyl-directed methanolysis of R-hydroxy esters. This species was initially
designed to act as a nucleophilic catalyst; however, we have ruled out a nucleophilic mechanism
by examining the activity of 6-substituted-FPP derivatives. These compounds are more hindered
in the vicinity of the pyridine nitrogen than FPP itself but are also more active catalysts.
Furthermore, the presence of p-nitrophenol, a mild acid, was found to accelerate the catalytic
reaction. These results are inconsistent with a nucleophilic catalysis mechanism. We provide
evidence that the reaction instead proceeds via dioxolanone intermediate 10. Dioxolanone 10 can
be obtained by treating either the p-nitrophenyl ester or the pentafluorophenyl ester of glycolic
acid with FPP in chloroform in the absence of methanol. It has been isolated, characterized, and
shown to be kinetically competent when subjected to the conditions of the catalytic reaction.
Sch em e 1
Hydroxyl-directed reactions play an important role in
organic synthesis.1 They enable chemists to conduct
reactions with high levels of stereochemical and regio-
chemical selectivity, in some cases with control of abso-
lute stereochemistry. The advantages of this strategy
have been widely recognized ever since the pioneering
work of Henbest2 and of Simmons and Smith,3 and
numerous reagents and catalysts have been developed
which take advantage of hydroxyl-direction in their
mechanism of action.1 To the best of our knowledge, all
of the catalysts that have been developed have a common
mechanistic feature in that the binding site for the
hydroxyl group is the same as the catalytic site for the
reaction. This imposes certain constraints on catalytic
systems and can be limiting in the design of new,
selective, hydroxyl-directed catalysts for organic synthe-
sis.4 One solution to this problem is to consider catalysts
which contain separate binding and catalytic sites (Scheme
1). This strategy offers greater flexibility in the design
of hydroxyl-directed catalysts and allows for the conver-
sion of known catalysts which are not hydroxyl-directed
into ones which are by the incorporation of a binding site.
To examine this strategy, we have studied the design
of hydroxyl-directed acyl-transfer catalysts. Specifically,
we wished to render the 4-aminopyridine class of nucleo-
philic acyl-transfer catalysts5 hydroxyl-directed by the
incorporation of a binding site. The requirements for a
binding site in this system are that it rapidly and
reversibly bind an alcohol, that it be stable to the reaction
conditions, and that it not be so Lewis acidic that the
catalyst undergoes intramolecular association between
the nucleophilic and electrophilic components or under-
goes dimerization. With these requirements in mind, we
have prepared 2-formyl-4-pyrrolidinopyridine (FPP, 1a ,
Scheme 2) in which an aldehyde at the 2-position of the
pyridine serves as the binding site.6 An aldehyde meets
the requirements outlined above in that it is a stable
functional group that can reversibly bind a hydroxyl
group by the formation of a hemiacetal,7 yet it is only
mildly electrophilic. At the 2-position of a pyridine it is
sterically encumbering and electron-withdrawing, thereby
deactivating the nucleophilic catalyst. FPP should, there-
fore, be a poor catalyst for the solvolysis of unfunction-
alized esters. However, upon binding of the hydroxyl
(1) For a review of substrate-directable reactions, see: Hoveyda, A.
H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93, 1307.
(2) Henbest, H. B.; Wilson, R. A. L. J . Chem. Soc. 1957, 1958
(3) Simmons, H. E.; Smith, R. D. J . Am. Chem. Soc. 1959, 81, 4256.
(4) In his account of the discovery of the asymmetric epoxidation,
Sharpless eloquently explains the limitations imposed by the require-
ment that the hydroxyl group of the substrate bind the metal which is
catalyzing the reaction and describes a series of ligands designed to
circumvent these limitations in asymmetric epoxidation reactions.
See: Sharpless, K. B. Chem. Br. 1988, 24, 38.
(5) For reviews, see: Scriven, E. F. V. Chem. Soc. Rev. 1983, 12,
129; Hassner, A.; Krepski, L. R.; Alexanian, V. Tetrahedron 1978, 34,
2069; Hofle, G.; Steglich, W.; Vorbruggen, H. Angew. Chem., Int. Ed.
Engl. 1978, 17, 569.
(6) For a preliminary account of this work, see: Sammakia, T.;
Hurley, T. B. J . Am. Chem. Soc. 1996, 118, 8967.
(7) For a review of hydration of aldehydes and ketones, see: Bell,
R. P. Adv. Phys. Org. Chem. 1966, 4, 1. (b) For a recent study of
carbonyl hydration equilibria, see: Wiberg, K. B.; Morgan, K. M.;
Maltz, H. J . Am. Chem. Soc. 1994, 116, 11067. (c) For a study of
hemiacetal formation of pyridine carboxaldehydes, see: Gianni, P.;
Matteoli, E. Gazz. Chim. Ital. 1975, 105, 125; and (d) Pocker, Y.;
Meany, J . E. Nist, B. J . J . Phys. Chem 1967, 71, 4509.
10.1021/jo982281n CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/06/1999

Mechanism of Action of 2-Formyl-4-pyrrolidinopyridine
J . Org. Chem., Vol. 64, No. 13, 1999 4653
F igu r e 1. Kinetic data for the methanolysis of p-nitrophenyl esters catalyzed by DMAP and FPP illustrating the preferential
reaction of p-nitrophenyl glycolate under FPP catalysis.
Sch em e 2
group of a hydroxy ester and formation of the corre-
sponding hemiacetal, the ester is brought into close
proximity to the pyridine nitrogen which can promote
acyl transfer and provide the product bound to the
catalyst.8 Dissociation of the product would regenerate
the catalyst ready to repeat the catalytic cycle. In this
article, we describe our studies on the mechanism of
action of FPP aimed at probing the validity of the design
features of the catalyst and deducing the role of the
aldehyde and of the pyridine nitrogen in the catalytic
cycle. We also report the isolation and characterization
of a reactive intermediate in the catalytic cycle.
Rea ctivity of F P P . We have studied the hydroxyl-
directed methanolysis of esters with FPP.6 Initial rates
of methanolysis of the p-nitrophenyl (PNP) esters of
propionic acid (2), methoxyacetic acid (3), and glycolic
acid (4) with 5 mol % DMAP or FPP were measured by
monitoring the disappearance of the ester as a function
of time. Methanolysis reactions were run at a concentra-
tion of 0.1 M ester, 0.005 M catalyst, and 1.0 M methanol-
d4 in CDCl3, and the progress of the reactions was
monitored by NMR. As expected, due to electronic and
hydrogen bonding effects, the R-alkoxy and R-hydroxy
esters are intrinsically more reactive than the propionate
ester (Figure 1, Table 1).9 Using DMAP, the relative
initial rates of methanolysis of 2, 3, and 4 are 30, 210,
and 690, respectively. However, using FPP under the
same conditions, the relative initial rates are 1.0, 5.3, and
510, respectively.10 Thus, with FPP, methanolysis of the
glycolate ester is 96 times faster than that of the
Ta ble 1. Rela tive Ra tes for th e Meth a n olysis of
p-Nitr op h en yl Ester s w ith DMAP a n d F P P Ca ta lysis
(8) The binding of the substrate to the catalyst converts the aldehyde
to a hemiacetal. An aldehyde is a more electron-withdrawing group
than a hemiacetal, and as such the bound substrate should encounter
a more active pyridine. An approximate measure of the electron-
withdrawing ability of these two groups in this system can be obtained
by comparing the pKa of pyridine 2-carboxaldehyde (3.8 in water) and
the hydrate of pyridine-2-carboxaldehyde (4.2 in water). This minor
difference in basicity indicates that while the hemiacetal is less
electron-withdrawing, the effect is relatively unimportant. See: Owens,
T. C. J . Heterocycl. Chem. 1990, 27, 987. Green, R. W.; Freer, I. R. J .
Phys. Chem. 1961, 65, 2211.
methoxyacetate, whereas with DMAP it is only 3 times
faster. This difference is primarily due to a 40-fold
decrease in the rate of the methanolysis of the PNP ester
of methoxyacetic acid (3) with FPP (krel ) 5.3) as
compared to DMAP (krel ) 210), which is consistent with
our proposed mechanism of action for FPP. It should be
noted that in the absence of a catalyst <1% reaction of
any of the p-nitrophenyl esters examined in this study
was observed after 120 h.
(9) Ingold, C. K. Structure and Mechanism in Organic Chemistry;
Cornell University Press: Ithaca, 1953; p 758.
(10) Under our standard reaction conditions (0.005 M FPP, 0.1 M
initial concentration of p-nitrophenyl glycolate, 1.0 M methanol-d4)
p-nitrophenyl glycolate is consumed at a rate of 0.029 M h-1
.

4654 J . Org. Chem., Vol. 64, No. 13, 1999
Sammakia and Hurley
Ta ble 2. Effect of Ca ta lyst Str u ctu r e on Rea ctivity
FPP is also an effective catalyst for the methanolysis
of esters that are less active than PNP esters. Under the
same conditions as in the previous study, the relative
rates of methanolysis of phenyl glycolate, p-fluorophenyl
glycolate, and p-nitrophenyl glycolate are 64, 140, and
510 with a half-life for the phenyl glycolate methanolysis
of 18 h. These relative rates are comparable to those
observed for simple alkaline hydrolysis.11
Mech a n istic Stu d ies. In our mechanistic studies, we
first wished to establish that all of the components of FPP
are required for catalytic activity. Toward this end we
have examined a number of FPP derivatives as catalysts
for the methanolysis of p-nitrophenyl glycolate (Table 2).
Compound 5, in which the carboxaldehyde has been
moved from the 2 to the 3 position on the pyridine, is
about 10 times less active than FPP and exhibits low
selectivity for the methanolysis of hydroxy esters over
methoxy esters, similar to that observed with DMAP. It
appears that the 3-carboxaldehyde is too far from the
pyridine nitrogen to act as a binding site for the hydroxy
ester substrate and that this catalyst operates by a
simple nucleophilic catalysis mechanism. Compound 6,
in which the aldehyde at the 2-position has been replaced
with an amide, is inactive due to the inability of the
amide to function as a binding site. In compound 7, the
amino group has been deleted from the 4-position. This
compound is inactive due to the decreased basicity of the
pyridine. Similarly, compound 8, in which the amino
substituent has been moved from the 4- to the 6-position
on the pyridine, is less basic and more hindered than
FPP, and therefore inactive.12,13
F igu r e 2. Examination of the effect of methanol concentration
from 0.5 to 8.0 M on the rate of the FPP-catalyzed methanoly-
sis of p-nitrophenyl glycolate.
acetal in an unproductive equilibrium and inhibit the
reaction. We therefore measured the rate of methanolysis
of p-nitrophenyl glycolate under conditions in which the
concentration of the substrate and catalyst was kept
constant while the concentration of methanol was varied.
We find that as the concentration of methanol is in-
creased, the rate of the reaction is retarded (Figure 2).
Consistent with this observation, in CDCl3 we find that
15% of FPP exists as the hemiacetal under our typical
reaction conditions in the absence of any substrate (1.0
M methanol-d4, 0.005 M FPP), whereas at higher con-
centrations of methanol (8.0 M methanol-d4, 0.005 M
FPP), 37% of FPP exists as the hemiacetal. At a lower
concentration of methanol (0.5 M methanol-d4, 0.005 M
FPP), only 11% of FPP exists as the hemiacetal.14
Confident that FPP is acting as a catalyst by formation
of a complex with the substrate, we turned our attention
to elucidating the next step of the mechanism. The
4-aminopyridine class of acyl transfer catalysts is well-
known to operate by a nucleophilic mechanism in which
the pyridine nitrogen attacks the carbonyl of an active
ester to provide an acylpyridinium species.5 This species
then undergoes attack by an alcohol to provide the
acylated product. The analogous mechanism with FPP
The dependence of the rate of the reaction on the
concentration of methanol provides further evidence for
the involvement of the aldehyde in the catalytic cycle.
Our mechanism requires the presence of the free alde-
hyde in the catalyst in order to form a hemiacetal with
the substrate. However, methanol can compete with the
substrate for the aldehyde and form the methyl hemi-
(11) The relative rate of simple alkaline hydrolysis of PNP and
phenyl esters is about 3.5:1, a value which is comparable to what we
observe with our catalyst. See: Menger, F. M.; Ladika, M. J . Am.
Chem. Soc. 1987, 109, 3145.
(12) In d4-methanol we do not detect the hemiacetal corresponding
to 5, demonstrating the lower electrophilicity of the 3-carboxaldehyde.
Compounds 7 and 8 exist as 1:1 and 6:1 ratios of hemiacetal to
aldehyde, respectively, indicating that the ability of the aldehyde to
reversibly form a hemiacetal is not a sufficient condition for catalysis.
(13) 4-Aminopyridines are about 2 pKa units more basic than the
comparable 2-aminopyridines. See: Schofield, K. Hetero-aromatic
Nitrogen Compounds, Pyrroles and Pyridines; Plenum Press: New
York, 1967; pp 145-150.
(14) Hemiacetal content in CDCl3 was measured by 1H NMR. In
water, 48% of 2-formylpyridine (6) exists as the hydrate (see refs 7c
and 7d). It is known that the equilibrium constants for the addition of
water to aldehydes and ketones are smaller than the corresponding
equilibrium constants for the addition of methanol; however, the origin
of this effect is not understood. See refs 7a and 7b.

Mechanism of Action of 2-Formyl-4-pyrrolidinopyridine
J . Org. Chem., Vol. 64, No. 13, 1999 4655
Sch em e 3
F igu r e 3. Effect of added p-nitrophenol on the FPP-catalyzed
rate of p-nitrophenyl glycolate methanolysis.
pyridine nitrogen and retard the reaction according to
the nucleophilic mechanism.5,16 In the event, we found
that the addition of 0.5 and 1.0 equiv of PNPOH provides
a 1.8 and 2.3-fold increase in the rate of the reaction,
respectively (Figure 3). Our inability to reconcile this
observation with the nucleophilic mechanism provides
indirect evidence against this mechanism, and we sought
a more definitive experiment to probe this issue.
To distinguish between the nucleophilic and general
base mechanisms we have examined the reactivity of FPP
derivatives which are sterically hindered in the vicinity
of the pyridyl nitrogen. In the case of typical nucleophilic
acyl transfer catalysts, steric hindrance in proximity to
the nucleophilic group is known to deactivate the cata-
lyst.5 For example, 2-methylpyridine (pKa ) 5.96) is more
basic than pyridine (pKa ) 5.23) but is 21 times less
active as a catalyst in the benzoylation of benzyl alcohol.
2,6-Lutidine (pKa ) 6.72) is 81 times less active than
pyridine in the same reaction.17 To quantify this effect
in the case of the 4-aminopyridine class of catalysts, we
examined the effectiveness of a series of 2-alkyl-4-
pyrrolidinopyridine (2-alkyl-4-PPY) derivatives as cata-
lysts in the acylation of menthol with acetic anhydride
(Table 3). Acylation with 1% PPY as a catalyst is rapid,
with complete conversion occurring in less than 2 h.
However, the introduction of a methyl group at the
2-position of the catalyst provides a 30-fold decrease in
the activity. Increasing the bulk of the alkyl substituent
further decreases catalyst activity, until 2-isopropyl-4-
PPY (12d ) and 2-tert-butyl-4-PPY (12e) show no rate
acceleration over the uncatalyzed reaction.
is shown in Scheme 3. In this mechanism (the “nucleo-
philic” mechanism), the catalytic cycle begins with the
addition of the alcohol of the hydroxy ester to the
aldehyde of FPP, providing hemiacetal 9. The pyridine
nitrogen then attacks the carbonyl of the ester to provide
the cyclic acylpyridinium species 11. This species under-
goes attack by methanol to provide the methyl ester
bound to the catalyst as the hemiacetal. Dissociation of
the hydroxy ester from the hemiacetal liberates the
product and regenerates the catalyst. However, an
alternative mechanism is also depicted in Scheme 3. In
this mechanism (the “general-base” mechanism), the
pyridine nitrogen acts as a base and deprotonates the
hydroxyl group of the hemiacetal.15 The hydroxyl group
then acts as a nucleophile and attacks the ester to form
dioxolanone 10. This species is then methanolyzed with
general base assistance from the pyridine nitrogen to
provide the methyl ester bound to the catalyst as the
hemiacetal. As in the previous mechanism, dissociation
of the hydroxy ester from the hemiacetal liberates the
product and regenerates the catalyst.
FPP was designed to operate as a nucleophilic catalyst
based on the previously mentioned nucleophilicity of the
4-aminopyridines. However, the nucleophilic mechanism
became suspect once we examined the effect of added
p-nitrophenol (PNPOH) on the reaction. PNPOH, which
is liberated during the course of the reaction, is a mild
acid (pKa ) 7.2) and should partially protonate the
These results indicate that if FPP were operating by a
nucleophilic mechanism, analogues which are hindered
in the vicinity of the pyridyl nitrogen should be less active
(16) The 1H NMR spectra of reactions in progress show significant
changes in the chemical shift of the pyridine protons as the reaction
proceeds. We attribute this to the release of PNPOH as the reaction
progresses, and partial protonation of the pyridine nitrogen. We have
not determined the pKa of PNPOH or our catalyst in CHCl3 and
therefore do not know the full extent of the interation between these
species.
(17) Bondarenko, L. I.; Kirichenko, A. I.; Litvinenko, L. M.; Dmi-
trenko, I. N.; Kobets, V. D. Zh. Org. Khim. 1981, 17, 2588. See also
ref 13, page 195.
(15) We estimate the pKa of the of the hydroxyl group of 9 to be
about 13 in analogy to the pKa of the hydrate of pyridine 2-carboxal-
dehyde which is known to be 12.6. Furthermore, we estimate the pKa
of the pyridine nitrogen of 9 to be about 8.5 based on the fact that the
corresponding pKa in the hydrate of pyridine 2-carboxaldehyde is about
1 pKa unit less than pyridine. See: Owen, T. C. J . Heterocycl. Chem.
1990, 27, 987.

4656 J . Org. Chem., Vol. 64, No. 13, 1999
Sammakia and Hurley
Ta ble 3. Effect of 2-Alk yl Su bstitu tion on th e Rea ctivity
of 4-P yr r olid in op yr id in e a s a n Acyl Tr a n sfer Ca ta lyst in
th e Acyla tion of Men th ol
Sch em e 4
Ta ble 4. Effect of 6-Su bstitu tion on F P P Rea ctivity in
th e Meth a n olysis of p-Nitr op h en yl Glycola te
amount of FPP in the absence of methanol, dioxolanone
10 would be produced (Scheme 4). We conducted this
experiment in CDCl3, monitored the reaction by 1H NMR,
and observed a new set of resonances that are consistent
with dioxolanone 10 and free PNPOH.19 These reso-
nances increased in intensity to a steady state within 20
min, with a corresponding decrease in the intensity of
the resonances for FPP and the PNP-ester of glycolic acid
(Figure 4). This reaction does not proceed to completion;
some of the starting glycolate ester remains in solution.
After several hours, the unreacted PNP-glycolate reacts
with dioxolanone 10 to form a dimer which reacts further
with 10 to form various glycolate oligomers. If this
reaction is repeated with the pentafluorophenyl ester of
glycolic acid in place of the PNP ester, dioxolanone 10 is
formed much more rapidly, and the reaction proceeds to
higher conversion. When dioxolanone 10 is prepared in
this way, it can be purified by rapid flash chromatogra-
phy to provide a mixture of FPP and dioxolanone 10
(Figure 5). We have not been able to isolate a pure sample
of 10 because it undergoes partial hydrolysis to FPP upon
flash chromatography.20 Attempts to independently syn-
thesize dioxolanone 10 by standard procedures including
the acid-catalyzed condensation of glycolic acid with
FPP21 or by the treatment of FPP with trimethylsilyl
(trimethylsilyloxy)acetate and catalytic TMSOTf 22 met
with failure, presumably due to the presence of the basic
pyridyl nitrogen.
than FPP. We therefore prepared a series of FPP deriva-
tives with substituents of varying steric bulk at the
6-position of the pyridine ring (compounds 1b-e, Table
4) and examined them as catalysts for the methanolysis
of p-nitrophenyl glycolate. Interestingly, 6-alkyl-, 6-silyl-,
or 6-amino-substitution significantly enhances the activ-
ity of the catalyst. Introduction of a methyl group at the
6-position (1b) is found to increase the activity of the
catalyst by a factor of 4, and the more electron-donating
TMS group (1e) is found to provide a 13-fold increase in
activity. Even the very hindered 1c shows activity similar
to FPP. The increase in activity of the substituted
pyridines is consistent with an increase in the basicity
of the pyridine nitrogen,18 thereby increasing the rate of
methanolysis of dioxolanone 10. The difference in activity
of compounds 1b and 1c can be attributed to a decrease
in the basicity of 1c due to steric inhibition to protona-
tion. These results allow us to definitively exclude the
nucleophilic mechanism for this process.
Isola tion of d ioxola n on e 10. The evidence provided
up to this point allows us to exclude the nucleophilic
mechanism, but does not provide evidence specifically in
favor of the general base mechanism. We have, therefore,
obtained spectroscopic and kinetic evidence for the exist-
ence of the dioxolanone 10. To observe dioxolanone 10
spectroscopically, we reasoned that if we were to treat
the PNP-ester of glycolic acid with a stoichiometric
We have examined the kinetic order of the reaction and
find that with FPP catalysis, the methanolysis of the
PNP-ester of glycolic acid is zero-order in substrate over
most of the course of the reaction (Figure 6). This result
is consistent with the rapid formation of a substrate-
catalyst complex (i.e., dioxolanone 10), followed by a
(19) Though the formation of 10 likely occurs through initial
formation of 9, we have not directly observed this intermediate.
(20) Dioxolanone 10 (as a mixture with FPP) has been characterized
by 1H NMR, 13C NMR, IR, and mass spectrometry.
(21) Use of either p-toluenesulfonic acid or boron trifluoride etherate
failed to provide the desired dioxolanone. For discussions on general
methods of 1,3-dioxolan-4-one formation, see: Farines, M.; Soulier, J .
Bull. Soc. Chim. Fr. 1970, 332. See also: Seebach, D.; Imwinkelried,
R.; Stucky, G. Angew. Chem., Int. Ed. Engl. 1986, 25, 178; Schreiber,
S. L.; Reagan, J . Tetrahedron Lett. 1986, 27, 2945; Greiner, A.;
Ortholand, J . Y. Bull. Soc. Chim. Fr. 1993, 130, 133.
(18) Introduction of alkyl groups to the pyridine nucleus results in
an increase of 0.5-0.85 pKa units per alkyl group. See: Ikekawa, N.;
Sato, Y.; Maeda, T. Chem. Pharm. Bull. 1954, 2, 205. See also ref 13.
The pKa of 2-(trimethylsilyl)pyridine is 6.63, an increase of ap-
proximately 1.4 units over pyridine. This is in contrast to the effect of
the trimethylsilyl group in benzoic acid where it is found to be electron-
withdrawing. See: Anderson, D., G.; Chipperfield, J . R.; Webster, D.
E. J . Organomet. Chem. 1968, 12, 323.
(22) Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980, 21,
1357. Hoye, T. R.; Peterson, B. H.; Miller, J . D. J . Org. Chem. 1987,
52, 1351. (b) Pearson, W. H.; Cheng, M. J . Org. Chem. 1987, 52, 1353.

Mechanism of Action of 2-Formyl-4-pyrrolidinopyridine
J . Org. Chem., Vol. 64, No. 13, 1999 4657
carbonyl of the dioxolane, leaving the pyridyl nitrogen
free to act as a general base.
In conclusion, we have obtained good evidence that
FPP catalyzes the methanolysis of the PNP ester of
glycolic acid via hemiacetal 9 and dioxolanone 10. We
have isolated and characterized 10 and shown that it
provides the methyl ester of glycolic acid and FPP when
subjected to the catalytic reaction conditions and that it
is kinetically competent. Hindered analogues of FPP have
been shown to be more effective catalysts than FPP, thus
enabling us to rule out a nucleophilic mechanism. Our
current mechanism, in which a hemiacetal hydroxyl
group acts as a nucleophile, is related to that proposed
by Menger for the mechanism of action of his aldehyde-
functionalized surfactants, in which a deprotonated gem-
diol is used as a nucleophile for the hydrolysis of active
esters.24
Exp er im en ta l Section
F igu r e 4. 1H NMR from 7.40 to 6.36 ppm of the reaction
depicted in Scheme 4. Spectra were taken every 20 s for the
first 20 min of the reaction.
Gen er a l. All moisture-sensitive reactions were conducted
under a nitrogen atmosphere in oven-dried glassware using
solvents purified according to standard procedures.25 Chloro-
form-d was freshly distilled from CaH2 before each metha-
nolysis experiment. Methanol-d4 was used as received. 1H
NMR spectra were obtained at 500 MHz and 13C NMR spectra
at 125 MHz in CDCl3, with chemical shifts reported in ppm
referenced to residual chloroform (7.24 ppm for 1H and 77.0
ppm for 13C). 19F NMR spectra were obtained at 270 MHz in
CDCl3 with chemical shifts reported relative to internal CFCl3
(0 ppm). Infrared spectra were recorded as thin films on NaCl
plates. 4-Pyrrolidinopyridine was purified by kugelrohr distil-
lation prior to use.
Men th ol Acyla tion . Kinetics were measured using ana-
lytical gas-liquid chromatography (GLC). GLC was performed
on a Hewlett-Packard 5890 Series II equipped with an Alltech
SE-54 column (30 m length, 0.32 mm i.d., 0.25 µm film
thickness) and a hydrogen carrier gas flow of 1.6 mL/min.
Initial column temperature was 80 °C and was increased to
155 °C at 5 °C/min for each analysis. Sample solutions were
0.05 M menthol, 0.5 M acetic anhydride, 0.5 M triethylamine,
0.05 M biphenyl (internal standard), and 5 × 10-4 M catalyst
with a total volume of 1000 µL. The excess of acetic anhydride
and triethylamine ensures pseudo-first-order kinetics. Reac-
tions were monitored at time intervals for at least 2.5 half-
lives. Plots of ln[menthol] were linear and kobsd was obtained
directly from the slope using least-squares analysis. Under our
analytical conditions, retention times (in minutes) are as
follows: menthol, 6.3; menthyl acetate, 8.7; biphenyl, 10.5.
Ester Meth a n olysis. Kinetics were measured using 1H
NMR to monitor the disappearance of the R-methylene proton
resonances of the ester starting material. The reactions were
run at 20 ( 1 °C. Samples of 600 µL total volume were
prepared directly in NMR tubes. All solutions were 0.1 M ester,
0.005 M catalyst, and 0.1 M p-methyl anisole as an internal
standard and 1.0 M methanol-d4 in deuteriochloroform solu-
tion. For the methanol dependence experiment, the concentra-
tion of methanol-d4 was varied from 0.5 to 8.0 M with the total
sample volume remaining constant. Rate constants kobsd were
calculated from the slope of a plot of [ester] as a function of
time using least-squares analysis. For the determination of
rate constants, between five and twelve data points were
obtained. Most reactions were monitored for at least four half-
lives, with the exception of those with half-lives greater than
2 days.
turnover-limiting decomposition of this intermediate to
products. As the substrate is consumed, the rate of
formation of dioxolanone 10 slows such that this rate is
comparable to the rate of its conversion to product. This
leads to some deviation from linearity in the zero-order
plot late in the reaction. Consistent with this analysis,
examination of 1H NMR spectra of 1a -g catalyzed
reactions in progress reveals that the resting state of the
catalyst is not the free aldehyde, rather it is the corre-
sponding dioxolanone.23
The kinetic competence of dioxolanone 10 was estab-
lished by determining the rate constant for the conversion
of 10 to methyl glycolate and comparing this with the
corresponding rate constant determined from the cata-
lytic reaction under single turnover conditions. Thus,
dioxolanone 10 was prepared from FPP and p-nitrophen-
yl glycolate (4) in the absence of methanol. Upon addition
of methanol to this species, methyl glycolate was pro-
duced in a first-order reaction with a first-order rate
constant of 1.9 h-1. The corresponding rate constant for
the catalytic cycle was obtained via a single-turnover
experiment using 1.5 equiv of FPP. Under these condi-
tions, consumption of 4 is rapid and is followed by a
slower formation of methyl glycolate. The first-order rate
constant for the formation of methyl glycolate under
these conditions is 2.0 h-1, thereby establishing the
kinetic competence of 10.
We have also found that the presence of 0.032 and 0.10
M PNPOH increases the rate of methanolysis of dioxol-
anone 10 by a factor of 1.7 and 2.9, respectively, consis-
tent with our observations of the effect of PNPOH on the
overall catalytic cycle. We attribute this effect to the
ability of PNPOH to protonate the nitrogen of 10, thereby
producing the pyridinium salt and the moderately basic
species p-nitrophenylate (Scheme 5). Even though this
species is less basic than the pyridine nitrogen, it is in a
stereoelectronically more favorable position to deproto-
nate the incoming methanol. Alternatively, PNPOH could
be acting as a general acid catalyst by protonating the
Sin gle Tu r n over Kin etics. A solution of FPP (0.050 M),
p-nitrophenyl glycolate (0.033 M), and methanol-d4 (1.0 M) in
CDCl3 was monitored by 1H NMR. Following a rapid and
(24) Menger, F. M.; Whitesell, L. G. J . Am. Chem. Soc. 1985, 107,
707.
(25) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory
Chemicals; Pergamon: Oxford, 1988.
(23) The dioxolanone was identified for each catalyst by the upfield
shifts of the pyridine aromatic protons and the appearance of the acetal
methine.

4658 J . Org. Chem., Vol. 64, No. 13, 1999
Sammakia and Hurley
F igu r e 5. 1H NMR of a 1.3:1 mixture of dioxolanone 10 and FPP isolated by flash chromatography.
F igu r e 6. Kinetic data for the methanolysis of p-nitrophenyl glycolate fitted to zero- and first-order plots. Arbitrary smooth
lines are drawn through the data.
quantitative conversion of the glycolate to dioxolanone 10, a
clean first-order methanolysis of 10 to methyl glycolate was
Syn th eses. FPP (1a ) and 6 were prepared as previously
described.6 Compound 7 was purchased from Aldrich Chemical
Co. and distilled prior to use. Compound 5 was prepared from
observed with kobs ) 2.0 h-1
.

Mechanism of Action of 2-Formyl-4-pyrrolidinopyridine
J . Org. Chem., Vol. 64, No. 13, 1999 4659
was prepared by treatment of PPY with tert-BuLi in heptane
Sch em e 5
at reflux (eq 4).28
Catalyst 1c was prepared from 12e by in situ treatment
with BF3 followed by metalation with tert-BuLi and trapping
with DMF (eq 5). A similar scheme was attempted to prepare
1b; however, the metalation of the BF3 complex of 2-methyl-
4-PPY proceeded in poor yield and was not reproducible. This
compound was instead prepared from the diisopropyl amide
of 6-methylpicolinic acid29 by the route shown in Scheme 7.
3-formyl-4-chloropyridine26 by treatment with pyrrolidine at
reflux (eq 1). Compound 8 was prepared from 2,6-dibromopyr-
idine by monosubstitution with pyrrolidine followed by meta-
Sch em e 7
lation with tert-BuLi and trapping with DMF (eq 2). Compound
12b was prepared from PPY by a modification of the method
of Kessar27 in which the in situ prepared BF3 complex was
metalated with n-BuLi and trapped with methyl iodide (eq 3)
followed by decomplexation in refluxing ethanol/potasium
carbonate.
Metalation with n-BuLi and trapping with iodine provided the
3-iodo derivative 14. This compound was subjected to the
“halogen dance” reaction of Queguiner30 to provide the 4-iodo
derivative 15. Substitution of the iodide of 15 for pyrrolidine
was accomplished in refluxing pyrrolidine to provide 16. The
amide of 16 was subjected to DIBAL reduction to provide 1b.
Compounds 12c and 12d were prepared as shown in Scheme
6 by metalating the BF3 complex of PPY with n-BuLi and
Sch em e 6
The synthesis of 1d proceeded via 2,6-diiodo-4-PPY (17,
Scheme 8) which was prepared from the amine oxide of PPY31
Sch em e 8
trapping with bromine to provide 2-bromo-4-PPY (13). This
compound was subjected to Stille coupling with either vinyl-
tributyltin or 2-(tributylstannyl)propene and then hydroge-
nated to provide 12c and 12d , respectively. Compound 12e
(28) Scalzi, F. V.; Golob, N. F. J . Org. Chem. 1971, 36, 2541.
(29) Green, M. J .; Britovsek, G. J . P.; Cavell, K. J .; Gerhards, F.;
Yates, B. F.; Frankcombe, K.; Skelton, B. W.; White, A. H. J . Chem.
Soc., Dalton Trans. 1998, 7, 1137.
(30) Rocca, P.; Cochennec, C.; Marsais, F.; Thomas-dit-Dumont, L.;
Mallet, M.; Godard, A.; Queguiner, G. J . Org. Chem. 1993, 58, 7832;
Giullier, F.; Nivolier, F.; Marsais, F.; Queguiner, G. Tetrahedron Lett.
1994, 35, 6489. For a review, see: Queguiner, G.; Marsais, F.; Snieckus,
V.; Epsztajn, J . In Advances in Heterocyclic Chemistry; Katritzky, A.
R., Ed.; Academic: San Diego, 1991; Vol 52; pp 187-295.
(31) Morkved, E. Acta Chem. Scand. Ser. B. 1979, 33, 433.
(26) Marsais, F., Trecourt, F., Breant, P., Queguiner, G. J . Hetero-
cycl. Chem. 1988, 25, 81.
(27) Kessar, S. V.; Singh, P.; Singh, K. N. Dutt, M. J . Chem. Soc.,
Chem. Commun. 1991, 570. (b) For the application of this method to
the metalation of DMAP, see: Vedejs, E.; Chen, X. J . Am. Chem. Soc.
1996, 118, 1809.

4660 J . Org. Chem., Vol. 64, No. 13, 1999
Sammakia and Hurley
2H), 0.93 (s, 9H), 0.14 (s, 6H). 13C NMR (CDCl3): δ 170.36,
150.36, 129.46, 125.92, 121.33, 61.85, 25.73, 18.40, -5.41. IR
2929.0, 1783.7, 1130.2, 839.8 cm-1. TLC Rf ) 0.54 (10:1
hexanes/ethyl acetate). HRMS (CI+, i-C4H10) m/z calcd for
C14H23O3Si [M + H]+ 267.1416, found 267.1409. Purity was
Sch em e 9
1
assayed by H NMR (see Supporting Information).
Gen er a l P r oced u r e for TBS Dep r otection of Glycola te
Ester s: p-Nitr op h en yl Glycola te (4). Aqueous hydrofluoric
acid (49 wt %, 6.0 mL, 191 mmol, 6.5 equiv) was added to a
solution of p-nitrophenyl (tert-butyldimethylsilyloxy)acetate
(9.140 g, 29.4 mmol, 1.0 equiv) in acetonitrile (150 mL), and
the solution was stirred overnight. The solution was diluted
with ethyl acetate and washed with brine (6×). The organic
phase was dried over MgSO4 and concentrated under reduced
pressure. Recrystallization from hexanes/methylene chloride
provided 5.786 g (85%) of p-nitrophenyl glycolate as a crystal-
line solid. 1H NMR (CDCl3): δ 8.28 (m, 2H), 7.32 (m, 2H), 4.48
(s, 2H). 13C NMR (CDCl3): δ 170.99, 154.60, 145.57, 125.34,
122.13, 60.72. IR (thin film) 3430.2, 1769.9, 1523.8, 1348.4,
1209.0 cm-1. TLC Rf ) 0.32 (1:1 hexanes/ethyl acetate).
p-Nitrophenyl glycolate is not stable to silica gel chromatog-
raphy. HRMS (CI+, i-C4H10) m/z calcd for C8H8NO5 [M + H]+
198.0402, found 198.0391. Purity was assayed by 1H NMR (see
Supporting Information).
Sch em e 10
by metalating with 4 equiv of LDA followed by treatment with
4 equiv of iodine.32 Reduction of the amine oxide was ac-
complished with PBr3 to provide 17. Monosubstitution of one
of the iodides of 17 for pyrrolidine was followed by metalation
of the remaining iodide with tert-BuLi and trapping with DMF.
Compound 1e was prepared from PPY as shown in Scheme 9
by in situ complexation with BF3 followed by metalation with
n-BuLi and trapping with TMSCl to give 18. The BF3 moiety
remains bound to the pyridine nitrogen in 18, and a second
metalation with tert-BuLi and trapping with DMF provides
1e.
1
p-F lu or op h en yl glycola te: H NMR (CDCl3): δ 7.07 (m,
4H), 4.41 (s, 2H), 2.35 (br s, 1H). 13C NMR (CDCl3): δ 171.98,
160.38 (d, J C-F ) 244.7 Hz), 145.81, 122.62 (d, J C-F ) 8.0 Hz),
116.22 (d, J C-F ) 23.9 Hz), 60.68. IR 3440.2, 1761.2, 1503.4,
1247.7, 1185.1 cm-1. TLC Rf ) 0.27 (2:1 hexanes/ethyl acetate).
HRMS (EI) m/z calcd for C8H7FO3 170.0379, found 170.0373.
Purity was assayed by 1H NMR (see Supporting Information).
p-Nitrophenyl propionate (2) and p-nitrophenyl methoxy-
acetate (3) were synthesized by a DCC-mediated coupling of
the carboxylic acid with p-nitrophenol. Esters of glycolic acid
were synthesized in a three-step reaction sequence from tert-
butyldimethylsilyl (tert-butyldimethylsilyloxy)acetate. Forma-
tion of the acid chloride by the method of Wissner33 (oxalyl
chloride, catalytic DMF) followed by reaction with p-nitrophe-
nol, p-fluorophenol, pentafluorophenol, or phenol in the pres-
ence of pyridine provides the TBS-protected glycolate esters
(Scheme 10). Deprotection with HF in acetonitrile followed by
crystallization from methylene chloride/hexanes or flash chro-
matography provides the R-hydroxy ester.
1
P en ta flu or op h en yl glycola te: H NMR (CDCl3): δ 4.57
(s, 2H). 13C NMR (CDCl3): δ 169.43, 60.10 (aromatic carbons
are observed as multiplets in the range of 120-150 ppm due
to extensive C-F coupling). IR 3402.1, 1806.5, 1518.3, 1086.5,
1004.8, 993.3 cm-1. TLC Rf ) 0.52 (2:1 hexanes/ethyl acetate).
Pentafluorophenyl glycolate is not stable to silica gel chroma-
tography. HRMS (CI+, i-C4H10) m/z calcd for C8H4F5O3 [M +
H]+ 243.0081, found 243.0090. Purity was assayed by 1H NMR
(see Supporting Information).
P h en yl glycola te: 1H NMR (CDCl3): δ 7.38 (m, 2H), 7.25
(m, 1H), 7.10 (m, 2H), 4.42 (s, 2H), 2.45 (br s, 1H). 13C NMR
(CDCl3): δ 171.97, 150.03, 129.56, 126.24, 121.15, 60.74. IR
3423.8, 1762.8, 1200.0, 1092.6 cm-1. TLC Rf ) 0.34 (2:1
hexanes/ethyl acetate). HRMS (EI) m/z calcd for C8H8O3
152.0473, found 152.0486. Purity was assayed by 1H NMR (see
Supporting Information).
p-Nitr op h en yl (ter t-bu tyld im eth ylsilyloxy)a ceta te: 1H
NMR (CDCl3): δ 8.26 (m, 2H), 7.29 (m, 2H), 4.51 (s, 2H), 0.92
(s, 9H), 0.14 (s, 6H). 13C NMR (CDCl3): δ 169.45, 155.03,
145.37, 125.24, 122.18, 61.69, 25.66, 18.35, -5.44. IR 2930.0,
1790.4, 1347.8, 1119.8, 839.4 cm-1. TLC Rf ) 0.38 (10:1
hexanes/ethyl acetate). HRMS (CI+, i-C4H10) m/z calcd for
C14H22NO5Si [M + H]+ 312.1267, found 312.1263. Purity was
P r ep a r a tion a n d Ch a r a cter iza tion of Dioxola n on e 10.
A solution of FPP (0.060 g, 0.34 mmol, 1.0 equiv) and
pentafluorophenyl glycolate (0.163 g, 0.67 mmol, 2.0 equiv) in
3.5 mL of ethanol-free chloroform was stirred for 15 min. The
solvent was removed under reduced pressure and the residue
subjected to rapid flash chromatography (ethyl acetate) pro-
viding 0.062 g of a mixture of 10 and FPP. Dioxolanone 10 is
invariably isolated as a mixture with FPP due to hydrolysis
of the dioxolanone during chromatography. Isolated mixtures
range in composition from 3:1 to 1:1 dioxolanone/FPP. Diox-
olanone 10: 1H NMR (CDCl3): δ 8.19 (d, J ) 5.8 Hz, 1H), 6.53
(d, J ) 2.4 Hz, 1H), 6.37 (s, 1H), 6.36 (dd, J ) 5.9, 2.4 Hz,
1H), 4.52 (A of AB, J ) 14.7, 1H), 4.36 (B of AB, J ) 14.7,
1H), 3.32 (m, 4H), 2.02 (m, 4H). 13C NMR (CDCl3): δ 171.37,
153.64, 152.33, 149.90, 107.64, 105.04, 103.86, 63.88, 47.10,
25.25. IR 1806.1, 1220.7, 1186.9 cm-1. TLC Rf (10) ) 0.46, Rf
(FPP) ) 0.34 (ethyl acetate). LRMS (EI) m/z (relative inten-
sity): 234 (12), 176 (100). HRMS (EI) m/z calcd for C12H14N2O3
234.1004, found 234.1007. Purity was assayed by 1H NMR (see
Supporting Information).
1
assayed by H NMR (see Supporting Information).
p-F lu or op h en yl (ter t-bu tyld im eth ylsilyloxy)a ceta te:
1H NMR (CDCl3): δ 7.04 (m, 4H), 4.47 (s, 2H), 0.93 (s, 9H),
0.13 (s, 6H). 13C NMR (CDCl3): δ 170.38, 160.25 (d, J C-F
244.7 Hz), 146.15, 122.73 (d, J C-F ) 8.8 Hz), 116.11 (d, J C-F
)
)
23.8 Hz), 61.75, 25.70, 18.38, -5.42. IR 2930.0, 1784.9, 1504.0,
1128.3, 838.8 cm-1. TLC Rf ) 0.54 (10:1 hexanes/ethyl acetate).
HRMS (CI+, i-C4H10) m/z calcd for C14H22FO3Si [M + H]+
285.1322, found 285.1317. Purity was assayed by 1H NMR (see
Supporting Information).
P en t a flu or op h en yl (ter t-b u t yld im et h ylsilyloxy)a ce-
1
ta te: H NMR (CDCl3): δ 4.59 (s, 2H), 0.92 (s, 9H), 0.13 (s,
6H). 13C NMR (CDCl3): δ 168.02, 61.06, 25.60, 18.32, -5.58
(aromatic carbons are observed as multiplets in the range of
120-150 ppm due to extensive C-F coupling). IR 2932.2,
1813.3, 1527.9, 1098.3, 995.5, 839.0 cm-1. TLC Rf ) 0.63 (10:1
hexanes/ethyl acetate). HRMS (CI+, i-C4H10) m/z calcd for
C
14H20F5O3Si [M + H]+ 357.0945, found 357.0956. Purity was
1
assayed by H NMR (see Supporting Information).
3-F or m yl-4-(p yr r olid in -1-yl)p yr id in e (5). A solution of
4-chloro-3-formylpyridine (0.116 g, 0.82 mmol) in pyrrolidine
(5 mL) was refluxed for 48 h after which time no starting
material remained by TLC. Pyrrolidine was removed under
reduced pressure leaving a yellow liquid which was taken up
in methylene chloride and washed with saturated sodium
carbonate (2×). The organic phase was dried over MgSO4 and
concentrated under reduced pressure. Purification by flash
P h en yl (ter t-bu t yld im et h ylsilyloxy)a cet a t e: 1H NMR
(CDCl3): δ 7.37 (m, 2H), 7.22 (m, 1H), 7.08 (m, 2H), 4.48 (s,
(32) For leading references concerning the metalation of pyridine
N-oxides, see: Mongin, O.; Rocca, P.; Thomas-dit-Dumont, L.; Trecourt,
F.; Marsais, F.; Godard, A.; Queguiner, G. J . Chem. Soc., Perkin Trans.
1 1995, 2503.
(33) Wissner, A.; Grudzinskas, C. J . Org. Chem. 1978, 43, 3972.

Mechanism of Action of 2-Formyl-4-pyrrolidinopyridine
J . Org. Chem., Vol. 64, No. 13, 1999 4661
chromatography (5:1 ethyl acetate/methanol) provided 0.046
g (32%) of 3-formyl-4-(pyrrolidin-1-yl)pyridine as a yellow
crystalline solid. 1H NMR (CDCl3): δ 9.97 (s, 1H), 8.60 (s, 1H),
8.20 (d, J ) 6.2 Hz, 1H), 6.54 (d, J ) 6.2 Hz, 1H), 3.35 (m,
4H), 1.99 (m, 4H). 13C NMR (CDCl3): δ 189.00, 156.27, 151.77,
151.67, 118.77, 108.80, 51.84, 25.68. ΙR 1733.3, 1668.2, 1594.1,
736.8 cm-1. TLC Rf ) 0.55 (methanol). HRMS (EI) m/z calcd
for C10H12N2 176.0950, found 176.0944. Purity was assayed
C10H14N2: C, 74.03; H, 8.70; N, 17.27. Found: C, 73.71; H,
8.88; N, 17.20.
2-Br om o-4-(p yr r olid in -1-yl)p yr id in e (13). Boron trifluo-
ride etherate (1.83 mL, 14.8 mmol, 1.1 equiv) was added to a
0 °C solution of 4-pyrrolidinopyridine (2.0 g, 13.5 mmol, 1.0
equiv) in tetrahydrofuran (100 mL). The resulting suspension
was stirred for 30 min and then cooled to -78 °C. n-
Butyllithium (1.56 M in hexanes, 13.8 mL, 21.6 mmol, 1.6
equiv) was added and the solution stirred for 30 min at -78
°C after which time bromine (1.11 mL, 21.6 mmol, 1.6 equiv)
was added. The solution was allowed to warm to room-
temperature overnight. Saturated sodium bicarbonate was
added followed by ethyl acetate. The aqueous phase was
extracted with ethyl acetate (2×), and the combined organic
extracts were dried over MgSO4 and concentrated under
reduced pressure. Purification by flash chromatography (1:1
hexanes/ethyl acetate) followed by recrystallization from ethyl
acetate provided 1.767 g (58%) of 2-bromo-4-(pyrrolidin-1-yl)-
1
by H NMR (see Supporting Information).
2-Br om o-6-(p yr r olid in -1-yl)p yr id in e. A solution of 2,6-
dibromopyridine (13.00 g, 54.9 mmol) in pyrrolidine (150 mL)
was heated to reflux for 10 min after which time no starting
material remained by TLC. Pyrrolidine was removed under
reduced pressure leaving a light brown solid. The solid was
dissolved in 2:1 ethyl acetate/methylene chloride and washed
with 1 M NaOH (2×). The organic phase was dried over MgSO4
and concentrated under reduced pressure. Purification by flash
chromatography (5:1 hexanes/ethyl acetate) provided 11.59 g
(93%) of 2-bromo-6-(pyrrolidin-1-yl)pyridine as a crystalline
1
pyridine as a crystalline solid. H NMR (CDCl3): δ 7.89 (d, J
) 5.9 Hz, 1H), 6.51 (d, J ) 2.2 Hz, 1H), 6.30 (dd, J ) 6.1 Hz,
2.4 Hz, 1H), 3.27 (m, 4H), 2.01 (m, 4H). 13C NMR (CDCl3): δ
153.18, 149.00, 142.59, 109.37, 106.63, 47.15, 25.22. IR 1591.8,
1505.7, 988.8, 808.8, 665.6 cm-1. TLC Rf ) 0.42 (1:1 hexanes/
ethyl acetate). LRMS (EI) m/z (relative intensity): 226 (100),
198 (12), 105 (15). HRMS (EI) m/z calcd for C9H10BrN2 [M -
H]+ 225.0028, found 225.0028. Purity was assayed by 1H NMR
(see Supporting Information).
1
solid. H NMR (CDCl3): δ 7.20 (tr, J ) 7.6 Hz, 1H), 6.62 (d, J
) 7.4 Hz, 1H), 6.20 (d, J ) 8.2 Hz, 1H), 3.41 (m, 4H), 1.97 (m,
4H). 13C NMR (CDCl3): δ 157.46, 140.66, 138.97, 113.99,
104.77, 46.97, 24.64. ΙR 2857.8, 1613.9, 1534.2, 767.7 cm-1
.
TLC Rf ) 0.63 (5:1 hexanes/ethyl acetate). HRMS (EI) m/z
calcd for C9H11BrN2 226.0106, found 226.0121. Purity was
1
assayed by H NMR (see Supporting Information).
2-F or m yl-6-(p yr r olid in -1-yl)p yr id in e (8). tert-Butyllith-
ium (1.83 M in pentane, 0.69 mL, 1.26 mmol, 2.4 equiv) was
added to a -78 °C solution of 2-bromo-6-(pyrrolidin-1-yl)-
pyridine (0.119 g, 0.52 mmol, 1.0 equiv) in tetrahydrofuran
(10 mL). The solution was stirred for 1 h. N,N-Dimethylform-
amide (58 µL, 0.73 mmol, 1.4 equiv) was added, and the
solution was allowed to warm to room temperature and stir
overnight. Saturated sodium bicarbonate was added followed
by ethyl acetate. The aqueous layer was extracted with
chloroform (2×), and the organic extracts were combined, dried
over MgSO4, and concentrated to a yellow solid. Purification
by flash chromatography (10:1 hexanes/ethyl acetate) provided
0.061 g (66%) 2-formyl-6-(pyrrolidin-1-yl)pyridine as a bright
yellow crystalline solid. 1H NMR (CDCl3): δ 9.87 (s, 1H), 7.51
(tr, J ) 7.6 Hz, 1H), 7.14 (d, J ) 7.1 Hz, 1H), 6.51 (d, J ) 8.4
4-(P yr r olidin -1-yl)-2-vin ylpyr idin e. A solution of 2-bromo-
4-(pyrrolidin-1-yl)pyridine (13) (0.074 g, 0.33 mmol, 1.0 equiv),
Pd2dba3 (0.015 g, 0.02 mmol, 0.05 equiv), tri-2-furylphosphine
(0.030 g, 0.13 mmol, 0.4 equiv), CuI (0.012 g, 0.07 mmol, 0.2
equiv), and vinyltributyltin (0.143 mL, 0.49 mmol, 1.5 equiv)
in N,N-dimethylacetamide (DMA, 1.6 mL) was heated to 85
°C for 24 h after which time no starting material remained by
TLC. DMA was removed under vacuum (0.4 mmHg) with
gentle heating. The residue was redissolved in methylene
chloride, and this solution was stirred vigorously with satu-
rated potassium fluoride solution for 3 h. The layers were
separated, and the aqueous phase was extracted with chloro-
form (3×). The combined organic extracts were dried over
MgSO4 and concentrated. Flash chromatography (1:1 ethyl
acetate/methanol, and then methanol) provided 0.030 g (53%)
4-(pyrrolidin-1-yl)-2-vinylpyridine as a yellow liquid. 1H NMR
(CDCl3): δ 8.15 (d, J ) 5.8 Hz, 1H), 6.67 (dd, J ) 10.7 Hz,
17.3 Hz, 1H), 6.37 (d, 2.4 Hz, 1H), 6.24 (dd, J ) 2.4 Hz, 5.8
Hz, 1H), 6.13 (dd, J ) 1.4 Hz, 17.5 Hz, 1H), 5.35 (dd, J ) 1.4
Hz, 10.7 Hz, 1H), 3.28 (m, 4H), 1.99 (m, 4H). 13C NMR: δ
155.31, 152.32, 149.24, 137.66, 116.92, 105.89, 104.84, 46.94,
25.26. ΙR 1594.2, 1540.8, 1389.9 cm-1. TLC Rf ) 0.54 (98:2
methanol/saturated ammonium hydroxide). HRMS (EI) m/z
calcd for C11H14N2 174.1157, found 174.1164. Purity was
Hz, 1H), 3.47 (m, 4H), 1.99 (m, 4H). 13C NMR (CDCl3):
δ
194.58, 157.34, 151.38, 137.24, 111.03, 109.76, 46.65, 25.43.
ΙR 2851.5, 1706.1, 1610.9, 1595.7, 792.6 cm-1. TLC Rf ) 0.50
(5:1 hexanes/ethyl acetate). HRMS (EI) m/z calcd for C10H12N2
176.0950, found 176.0966. Purity was assayed by 1H NMR (see
Supporting Information).
2-Meth yl-4-(p yr r olid in -1-yl)p yr id in e (12b). Boron tri-
fluoride etherate (0.23 mL, 1.86 mmol, 1.1 equiv) was added
to a 0 °C solution of 4-pyrrolidinopyridine (0.250 g, 1.69 mmol,
1.0 equiv) in tetrahydrofuran (20 mL). The resulting suspen-
sion was stirred for 30 min and then cooled to -78 °C.
n-Butyllithium (1.60 M in hexanes, 1.69 mL, 2.99 mmol, 1.6
equiv) was added and the solution stirred for 30 min at -78
°C after which time methyl iodide (0.21 mL, 3.37 mmol, 2.0
equiv) was added. The solution was stirred at -78 °C for 1 h
and was then allowed to warm to room temperature and stir
for another 2 h. Saturated sodium bicarbonate was added
followed by ethyl acetate. The layers were separated, and the
organic phase was dried over MgSO4 and concentrated under
reduced pressure to a yellow solid. The solid was dissolved in
absolute ethanol (20 mL) with potassium carbonate (1.165 g,
5.0 equiv) and heated to reflux for 30 min. After cooling to
room temperature, the solvent was removed and the residue
extracted with methylene chloride (4×). The extracts were
filtered through Celite, and solvent was removed under
reduced pressure. Purification by flash chromatography (metha-
nol) provided 0.223 g (82%) of 2-methyl-4-(pyrrolidin-1-yl)-
1
assayed by H NMR (see Supporting Information).
2-Eth yl-4-(p yr r olid in -1-yl)p yr id in e (12c). A solution of
4-(pyrrolidin-1-yl)-2-vinylpyridine (0.058 g, 0.33 mmol) and 5%
palladium on carbon (0.010 g) in absolute ethanol (4 mL) was
stirred under an atmosphere of hydrogen (balloon) for 12 h.
The solution was filtered through
a plug of Celite and
concentrated under reduced pressure. Flash chromatography
(methanol, then 20:1 methanol/triethylamine) provided 0.053
g (90%) of 2-ethyl-4-(pyrrolidin-1-yl)pyridine as a yellow liquid.
1H NMR (CDCl3): δ 8.12 (d, J ) 5.8 Hz, 1H), 6.22 (dd, J ) 2.3
Hz, 1H), 6.20 (dd, J ) 5.9 Hz, 2.5, Hz, 1H), 3.28 (m, 4H), 2.67
(q, J ) 7.5 Hz, 2H), 1.99 (m, 4H), 1.26 (tr, J ) 7.6 Hz, 3H). 13
C
NMR: δ 163.23, 152.27, 148.98, 104.62, 104.52, 46.82, 31.56,
25.23, 14.03. ΙR 2966.2, 1601.5, 1542.7, 1502.5, 1388.7 cm-1
.
TLC Rf ) 0.47 (98:2 methanol/saturated ammonium hydrox-
ide). HRMS (EI) m/z calcd for C11H15N2 [M-H]+ 175.1235,
1
found 175.1235. Purity was assayed by H NMR (see Support-
ing Information).
1
pyridine as a crystalline solid. H NMR (CDCl3): δ 8.08 (d, J
2-(2-P r op en yl)-4-(p yr r olid in -1-yl)p yr id in e: A solution
of 2-bromo-4-(pyrrolidin-1-yl)pyridine (13) (0.649 g, 2.86 mmol,
1.0 equiv), Pd2dba3 (0.131 g, 0.15 mmol, 0.05 equiv), tri-2-
furylphosphine (0.266 g, 1.14 mmol, 0.4 equiv), CuI (0.109 g,
0.57 mmol, 0.2 equiv), and 2-(tributylstannyl)propene (1.42 g,
4.29 mmol, 1.5 equiv) in N,N-dimethylacetamide (DMA, 14
) 5.9 Hz, 1H), 6.22 (d, J ) 2.3 Hz, 1H), 6.20 (dd, J ) 5.9 Hz,
2.4 Hz, 1H), 3.27 (m, 4H), 2.41 (s, 3H), 1.99 (m, 4H). 13C
NMR: δ 157.90, 152.19, 148.90, 105.77, 104.53, 46.86, 25.28,
24.62. ΙR 1606.2, 1507.8, 1387.7 cm-1. TLC Rf ) 0.31 (98:2
methanol/saturated ammonium hydroxide). Anal. Calcd for

4662 J . Org. Chem., Vol. 64, No. 13, 1999
Sammakia and Hurley
mL) was heated to 85 °C for 48 h after which time no starting
material remained by TLC. The solution was diluted with 1:1
ethyl acetate/methylene chloride and extracted with 1 M HCl
until the extracts were colorless (6×). The aqueous extracts
were washed with hexanes and basified to pH 12 by the
addition of 5 M NaOH. The basic aqueous solution was then
extracted with chloroform (6×) and concentrated under re-
duced pressure to give a green liquid. Residual DMA was
removed by gentle heating of the liquid while under vacuum
(0.4 mmHg). Flash chromatography (methanol) of the resultant
residue provided 0.261 g (49%) of 2-(2-propenyl)-4-(pyrrolidin-
1-yl)pyridine as a yellow crystalline solid. 1H NMR (CDCl3):
δ 8.18 (d, J ) 5.8 Hz, 1H), 6.52 (d, J ) 2.3 Hz, 1H), 6.28 (dd,
J ) 5.8 Hz, 2.4 Hz, 1H), 5.76 (s, 1H), 5.19 (s, 1H), 3.31 (m,
4H), 2.17, (s, 3H), 2.01 (m, 4H). 13C NMR (CDCl3): δ 148.44,
142.22, 148.81, 144.06, 114.60, 105.65, 103.06, 46.95, 25.29,
20.75. ΙR 1596.8, 1542.2, 1484.4 cm-1. TLC Rf ) 0.66 (98:2
methanol/saturated ammonium hydroxide). HRMS (EI) m/z
calcd for C12H16N2 188.1313, found 188.1337. Purity was
(10:1 hexanes/ethyl acetate) provided 4.09 g 3-iodo-6-methyl-
N,N,-diisopropyl-2-pyridinecarboxamide (73%) as an off-white
1
solid. H NMR (CDCl3): δ 7.91 (d, J ) 8.0 Hz, 1H), 6.82 (d, J
) 8.3 Hz, 1H), 3.51 (sept, J ) 7.0 Hz, 1H), 3.41 (sept, J ) 6.7
Hz, 1H), 2.45 (s, 3H), 1.56 (br d, J ) 7.0 Hz, 6H), 1.16 (br d,
J ) 6.7 Hz, 6H). 13C NMR (CDCl3): δ 168.07, 158.53, 157.84,
146.47, 124.22, 85.47, 50.98, 45.95, 23.88, 20.57, 20.23. IR
1634.6, 1324.1 cm-1. Rf ) 0.42 (1:1 hexanes/ethyl acetate).
Anal. Calcd for C13H19N2OI: C, 45.08; H, 5.53; N, 8.09.
Found: C, 45.98; H, 5.70; N, 8.14.
4-Iod o-6-m et h yl-N,N,-d iisop r op yl-2-p yr id in eca r b ox-
a m id e (15). n-Butyllithium (1.6 M in hexanes, 7.6 mL, 12.1
mmol, 1.1 equiv) was added to a 0 °C solution of diisopropyl-
amine (1.7 mL, 13.2 mmol, 1.2 equiv) in tetrahydrofuran (100
mL). The solution was allowed to stir for 20 min at 0 °C and
was then cooled to -78 °C. A solution of 3-iodo-6-methyl-N,N-
diisopropyl-2-pyridinecarboxamide (14) (3.82 g, 11.0 mmol, 1.0
equiv) in tetrahydrofuran (100 mL) was added dropwise via
cannula over 10 min. The dark red solution was stirred at -78
°C for 3 h, quenched with H2O (0.4 mL, 22.0 mmol, 2.0 equiv),
and then allowed to warm to room temperature over 2 h. The
reaction mixture was diluted with diethyl ether, washed with
brine (2×), dried over MgSO4, and concentrated under reduced
pressure to a brown solid. Purification by flash chromatogra-
phy (5:1 hexanes/ethyl acetate) provided 1.68 g of 4-iodo-6-
methyl-N,N,-diisopropyl-2-pyridinecarboxamide (44%) as a
crystalline solid. 1H NMR (CDCl3): δ 7.56 (d, J ) 0.8 Hz, 1H),
7.50 (d, J ) 1.1 Hz, 1H), 3.75 (sept, J ) 6.7 Hz, 1H), 3.48 (sept,
J ) 7.0 Hz, 1H), 2.44 (s, 3H), 1.49 (br d, J ) 7.0, 6H), 1.13 (br
d, J ) 6.7, 6H). 13C NMR (CDCl3): δ 167.24, 158.43, 156.10,
132.14, 127.90, 106.13, 50.67, 46.01, 23.89, 20.57, 20.34. IR
1633.1, 1561.9 cm-1. Rf ) 0.68 (1:1 hexanes/ethyl acetate).
Anal. Calcd for C13H19N2OI: C, 45.08; H, 5.53; N, 8.09.
Found: C, 45.14; H, 5.59; N, 8.14.
1
assayed by H NMR (see Supporting Information).
2-Isop r op yl-4-(p yr r olid in -1-yl)p yr id in e (12d ). A solution
of 2-(2-propenyl)-4-(pyrrolidin-1-yl)pyridine (0.040 g, 0.21 mmol)
and 5% palladium on carbon (0.007 g) in absolute ethanol (2
mL) was stirred under an atmosphere of hydrogen (balloon)
for 12 h. The solution was filtered through a plug of Celite
and concentrated under reduced pressure. Flash chromatog-
raphy (methanol, then 20:1 methanol/triethylamine) provided
0.038 g (95%) of 2-isopropyl-4-(pyrrolidin-1-yl)pyridine as a
yellow liquid. 1H NMR (CDCl3): δ 8.13 (d, J ) 5.4 Hz, 1H),
6.21 (m, 2H), 3.30 (m, 4H), 2.91 (sept, J ) 6.7 Hz, 1H), 1.99
(m, 4H), 1.26 (d, J ) 7.0 Hz, 6H). 13C NMR (CDCl3): δ 167.02,
152.30, 148.78, 104.75, 103.12, 46.86, 36.38, 25.25, 22.60. ΙR
2962.0, 1601.2, 1542.5, 1484.6, 1388.9 cm-1. TLC Rf ) 0.47
(98:2 methanol/saturated ammonium hydroxide). HRMS (EI)
m/z calcd for C12H17N2 [M - H]+ 189.1392, found 189.1392.
Purity was assayed by 1H NMR (see Supporting Information).
2-ter t-Bu tyl-4-(p yr r olid in -1-yl)p yr id in e (12e). tert-Bu-
tyllithium (1.83 M in pentane, 11.1 mL, 20.2 mmol, 1.5 equiv)
was added dropwise over 30 min to a -78 °C suspension of
4-pyrrolidinopyridine (2.00 g, 13.5 mmol, 1.0 equiv) in heptane
(15 mL) in a three-neck flask. The lavender solution was
stirred at -78 °C for 15 min and then allowed to warm to room
temperature. While outgassing with N2, the flask was fitted
with a short path distillation head and pentane was removed
by distillation. The distillation head was replaced with a reflux
condenser and the solution refluxed for 1 h after which time
it was allowed to cool to room temperature. Excess tert-
butyllithium was quenched by slow addition of water. The
solution was diluted with hexanes, and the layers were
separated. The aqueous layer was extracted with chloroform
(3×), and the combined organic extracts were dried over
MgSO4 and concentrated under reduced pressure to an orange
liquid. Purification by flash chromatography (1:1 ethyl acetate/
methanol) provided 2.057 g (74%) of 2-tert-butyl-4-(pyrrolidin-
6-Met h yl-4-(p yr r olid in -1-yl)-N,N,-d iisop r op yl-2-p yr i-
d in eca r boxa m id e (16). A solution of 4-iodo-6-methyl-N,N-
diisopropyl-2-pyridinecarboxamide (15) (1.41 g, 4.1 mmol) in
pyrrolidine (100 mL) was refluxed for 12 h. Pyrrolidine was
removed under reduced pressure leaving a dark orange
residue. The residue was dissolved in ethyl acetate, washed
with 1 N NaOH (2×) and brine, dried over MgSO4, and
concentrated under reduced pressure to an orange oil. Puri-
fication by flash chromatography (ethyl acetate, then 5:1 ethyl
acetate/methanol) provided 1.12 g of 6-methyl-4-(pyrrolidin-
1-yl)-N,N,-diisopropyl-2-pyridinecarboxamide (95%) as an off-
white solid. 1H NMR (CDCl3): δ 6.29 (d, J ) 2.1 Hz, 1H), 6.18
(d, J ) 2.1 Hz, 1H), 3.85 (sept, J ) 6.7 Hz, 1H), 3.27 (sept, J
) 6.7 Hz, 1H), 3.27 (m, 4H), 2.39 (s, 3H), 1.97 (m, 4H), 1.52
(br d, J ) 7.0 Hz, 6H), 1.13 (br d, J ) 6.7 Hz, 6H). 13C NMR
(CDCl3): δ 170.04, 157.49, 156.33, 152.57, 105.23, 102.07,
50.41, 46.98, 45.70, 25.27, 24.72, 20.68, 20.60. IR 1603.3 cm-1
Rf ) 0.6 (streak, 5:1 ethyl acetate/methanol). Anal. Calcd for
17H27N3O: C, 70.54; H, 9.41; N, 14.53. Found: C, 70.79; H,
.
C
9.58; N, 14.45.
1
1-yl)pyridine as a crystalline solid. H NMR (CDCl3): δ 8.18
2-F or m yl-6-m eth yl-4-(p yr r olid in -1-yl)p yr id in e (1b). Di-
isobutylaluminum hydride (1.0 M in hexanes, 1.56 mL, 1.58
mmol, 1.1 equiv) was added to a -78 °C solution of 6-methyl-
4-(pyrrolidin-1-yl)-N,N,-diisopropyl-2-pyridinecarboxamide (16)
(0.415 g, 1.43 mmol, 1.0 equiv) in tetrahydrofuran (20 mL).
The solution was stirred for 15 min at -78 °C, warmed to 0
°C, stirred for 30 min, and finally warmed to room temperature
and stirred for 1 h. The reaction was quenched by addition 5
N NaOH (1 mL) with vigorous stirring. The solution was
filtered through MgSO4 and concentrated to a brown solid.
Purification by flash chromatography (ethyl acetate) provided
0.184 g of 2-formyl-6-methyl-4-(pyrrolidin-1-yl)pyridine (67%)
(d, J ) 5.8 Hz, 1H), 6.29 (d, J ) 2.3 Hz, 1H), 6.20 (dd, J ) 5.8
Hz, 2.4 Hz, 1H), 3.30 (m, 4H), 1.99 (m, 4H), 1.33 (s, 9H). 13C
NMR (CDCl3): δ 169.12, 152.13, 148.60, 104.29, 101.80, 46.85,
37.05, 30.19, 25.26. ΙR 2953.5, 1599.4, 1483.5 cm-1. TLC Rf )
0.60 (98:2 methanol/saturated ammonium hydroxide). Anal.
Calcd for C13H20N2: C, 76.42; H, 9.87; N, 13.71. Found: C,
76.48; H, 9.90; N, 13.87.
3-Iod o-6-m et h yl-N,N,-d iisop r op yl-2-p yr id in eca r b ox-
a m id e (14). n-Butyllithium (1.6 M in hexanes, 11.1 mL, 17.7
mmol, 1.1 equiv) was added dropwise to a -78 °C solution of
6-methyl-N,N,-diisopropyl-2-pyridinecarboxamide (3.54 g, 16.07
mmol, 1.0 equiv) in tetrahydrofuran (100 mL). The reaction
mixture was stirred for 1.5 h, after which time a solution of
iodine (4.89 g, 19.28 mmol, 1.2 equiv) in tetrahydrofuran (50
mL) was added via cannula. The reaction mixture was then
allowed to warm to room temperature over 2 h. The reaction
mixture was diluted with diethyl ether and washed with
saturated sodium bisulfite (2×) and brine. The organic phase
was dried over MgSO4 and concentrated under reduced pres-
sure to a brown solid. Purification by flash chromatography
1
as a light yellow solid. H NMR (CDCl3): δ 9.94 (s, 1H), 6.90
(d, J ) 2.4 Hz, 1H), 6.39 (d, J ) 2.4 Hz, 1H), 3.33 (m, 4H),
2.50 (s, 3H), 2.02 (m, 4H). 13C NMR (CDCl3): δ 194.88, 158.68,
152.57, 152.53, 109.38, 102.97, 47.17, 25.25, 24.41. IR 1706.5,
1606.3, 1495.6 cm-1. Rf ) 0.5 (5:1 ethyl acetate/methanol).
Anal. Calcd for C11H14N2O: C, 69.43; H, 7.42; N, 14.73.
Found: C, 69.21; H, 7.57; N, 14.55.
2-ter t-Bu tyl-6-for m yl-4-(p yr r olid in -1-yl)p yr id in e (1c).
Boron trifluoride etherate (89 µL, 0.73 mmol, 1.2 equiv) was

Mechanism of Action of 2-Formyl-4-pyrrolidinopyridine
J . Org. Chem., Vol. 64, No. 13, 1999 4663
added to a 0 °C solution of 2-tert-butyl-4-(pyrrolidin-1-yl)-
pyridine (12e) (0.125 g, 0.61 mmol, 1.0 equiv) in tetrahydro-
furan (10 mL). The resulting suspension was stirred for 30
min and then cooled to -78 °C. tert-Butyllithium (1.83 M in
pentane, 0.55 mL, 0.97 mmol, 1.6 equiv) was added slowly.
The burgundy colored solution was stirred at -78 °C for 5 h
after which time N,N-dimethylformamide (95 µL, 1.2 mmol,
2.0 equiv) was added. The reaction was allowed to warm to
room temperature and stirred for 2 h. Saturated sodium
bicarbonate was added followed by ethyl acetate. The organic
layer was dried over MgSO4 and concentrated under reduced
pressure to an orange crystalline solid consisting of a 1.5:1
ratio of desired product to starting material. Purification by
flash chromatography (ethyl acetate) provided 0.054 g (38%)
of 2-tert-Butyl-6-formyl-4-(pyrrolidin-1-yl)pyridine as a yellow
crystalline solid. 1H NMR (CDCl3): δ 9.94 (s, 1H), 6.88 (d, J )
2.2 Hz, 1H), 6.55 (d, J ) 2.4 Hz, 1H), 3.34 (m, 4H), 2.02 (m,
4H), 1.36 (s, 9H). 13C NMR (CDCl3): δ 195.94, 169.86, 152.64,
152.41, 105.47, 102.01, 47.23, 37.36, 30.16, 25.33. ΙR 2967.4,
1701.0, 1607.9, 1482.8 cm-1. TLC Rf ) 0.40 (5:1 hexanes/ethyl
acetate). Anal. Calcd for C14H20N2O: C, 72.38; H, 8.68; N,
12.06. Found: C, 72.30; H, 8.81; N, 12.07.
crystalline solid. 1H NMR (CDCl3): δ 6.24 (d, J ) 1.7 Hz, 1H),
5.18 (d, J ) 1.7 Hz, 1H), 3.36 (m, 4H), 3.22 (m, 4H), 1.93 (m,
8H). 13C NMR (CDCl3): δ 157.50, 153.42, 117.87, 107.66, 86.11,
47.00, 46.67, 25.40, 25.20. ΙR 1590.7, 1512.2, 1457.8 cm-1. TLC
Rf ) 0.53 (5:1 hexanes/ethyl acetate). Anal. Calcd for C13H18
-
IN3: C, 45.49; H, 5.29; N, 12.24. Found: C, 45.42; H, 5.16; N,
12.21.
2-F or m yl-4,6-d i(p yr r olid in -1-yl)p yr id in e (1d ). tert-Bu-
tyllithium (1.7 M in pentane, 0.22 mL, 0.37 mmol, 2.2 equiv)
was added to a -78 °C solution of 2-iodo-4,6-di(pyrrolidin-1-
yl)pyridine (0.058 g, 1.7 mmol, 1.0 equiv) in diethyl ether (5
mL). The solution was stirred for 40 min and N,N-dimethyl-
formamide (20 µL) was added. The solution was allowed to
warm to room-temperature overnight. Saturated sodium bi-
carbonate was added followed by ethyl acetate. The organic
layer was dried over MgSO4 and concentrated under reduced
pressure. Purification by flash chromatography (5:1 hexanes/
ethyl acetate) provided 0.012 g of 2-formyl-4,6-di(pyrrolidin-
1-yl)pyridine (41%) as a yellow crystalline solid. 1H NMR
(CDCl3): δ 9.83 (s, 1H), 6.56 (d, J ) 2.0 Hz, 1H), 5.45 (d, J )
2.0 Hz, 1H), 3.47 (m, 4H), 3.32 (m, 4H), 1.98 (m, 8H). 13C NMR
(CDCl3): δ 195.65, 158.70, 153.21, 151.75, 97.39, 90.53, 47.22,
2,6-Diiod o-4-(p yr r olid in -1-yl)p yr id in e N-Oxid e. n-Bu-
tyllithium (1.56 M in hexanes, 31 mL, 48.7 mmol, 4.0 equiv)
was added to a -78 °C solution of diisopropylamine (7.2 mL,
51.2 mmol, 4.2 equiv) in tetrahydrofuran (20 mL). After
addition, the cold bath was removed and the solution allowed
to warm to room temperature. The LDA solution was then
added dropwise over 20 min to a -78 °C suspension of
4-(pyrrolidin-1-yl)pyridine N-oxide (2.00 g, 12.2 mmol, 1.0
equiv) in tetrahydrofuran (200 mL), and the solution was
stirred for 1 h. Iodine (12.4 g, 48.7 mmol, 4.0 equiv) was added
as a solution in tetrahydrofuran (20 mL). The solution was
allowed to slowly warm to room temperature and stir over-
night. The solution was washed with saturated sodium thio-
sulfate (3×) and saturated sodium carbonate (6×). The aque-
ous washes were extracted with chloroform (2×). The combined
organic extracts were dried over MgSO4 and concentrated
under reduced pressure. Flash chromatography (90:10 acetone/
chloroform, then 85:10:5 acetone/chloroform/methanol) pro-
vided 2.91 g of 2,6-diiodo-4-(pyrrolidin-1-yl)pyridine N-oxide
46.77, 25.50, 25.29. ΙR 1704.2, 1600.6, 1536.0, 1481.5 cm-1
TLC Rf ) 0.26 (5:1 hexanes/ethyl acetate). Anal. Calcd for
14H19N3O: C, 68.54; H, 7.81; N, 17.13. Found: C, 68.66; H,
.
C
7.82; N, 17.14.
2-(Tr im eth ylsilyl)-4-(pyr r olidin -1-yl)pyr idin e bor on tr i-
flu or id e com p lex (18). Boron trifluoride etherate (0.91 mL,
7.4 mmol, 1.1 equiv) was added to a 0 °C solution of 4-pyrrol-
idinopyridine (1.00 g, 6.4 mmol, 1.0 equiv) in tetrahydrofuran
(40 mL). The resulting suspension was stirred for 30 min and
then cooled to -78 °C. n-Butyllithium (1.56 M in hexanes, 6.9
mL, 10.8 mmol, 1.6 equiv) was added and the solution stirred
for 30 min at -78 °C after which time chlorotrimethylsilane
(2.14 mL, 16.8 mmol, 2.5 equiv) was added. The cold bath was
removed, and the solution was allowed to warm to room
temperature over 2 h. Saturated sodium bicarbonate was
added followed by ethyl acetate. The aqueous layer was
extracted with ethyl acetate (3×). The combined organic
extracts were dried over MgSO4 and concentrated under
reduced pressure. Purification by flash chromatography (ethyl
acetate) provided 1.341 g (69%) of 2-(trimethylsilyl)-4-(pyrrol-
idin-1-yl)pyridine boron trifluoride complex as a crystalline
1
(57%) as a yellow solid. H NMR (CDCl3): δ 6.96 (s, 2H), 3.23
(m, 4H), 2.02 (m, 4H). 13C NMR (CDCl3): δ 144.35, 119.19,
107.78, 47.70, 25.38. ΙR 1601.8, 1475.8, 1455.1, 1205.0 cm-1
.
1
solid. H NMR (CDCl3): δ 8.35 (m, 1H), 6.77 (d, J ) 2.8 Hz,
TLC Rf ) 0.43 (5:1 ethyl acetate/methanol). HRMS (EI) m/z
1H), 6.42 (dd, J ) 7.1 Hz, 2.9 Hz, 1H), 3.42 (br m, 4H), 2.09
(m, 4H), 0.40 (s, 9H). 13C NMR (CDCl3): δ 160.73, 152.05,
144.77, 115.29, 105.86, 47.64, 47.38, 25.19, 0.31. 19F NMR
(CDCl3) 67.94 (q, J B-F ) 15.3 Hz). ΙR 1620.2, 1112.6, 1078.5,
917.0, 851.5 cm-1. TLC Rf ) 0.47 (1:1 hexanes/ethyl acetate).
HRMS (EI, CI+ or CI-): only the decomplexed 2-(trimethyl-
silyl)-4-(pyrrolidin-1-yl)pyridine is observed; (EI) m/z calcd for
calcd for C9H10I2N2O 415.8883, found 415.8852. Purity was
1
assayed by H NMR (see Supporting Information).
2,6-Diiod o-4-(p yr r olid in -1-yl)p yr id in e (17). Phosphorus
tribromide (89 µL, 0.94 mmol, 3.0 equiv) was added slowly to
a 0 °C solution of 2,6-diiodo-4-(pyrrolidin-1-yl)pyridine N-oxide
(0.130 g, 0.31 mmol, 1.0 equiv) in ethanol-free chloroform (5
mL). The resultant slurry was brought to reflux for 3 h. The
solution was cooled to room temperature and poured into a 0
°C solution of sodium bicarbonate (20 mL). Ethyl acetate was
added, and the layers were separated. The aqueous phase was
extracted with ethyl acetate (3×). The combined organic
extracts were dried over MgSO4 and concentrated under
reduced pressure. Flash chromatography (4:1 hexanes/ethyl
acetate) provided 0.063 g (50%) 2,6-diiodo-4-(pyrrolidin-1-yl)-
pyridine as a crystalline solid. 1H NMR (CDCl3): δ 6.74 (s,
2H), 3.21 (m, 4H), 1.99 (m, 4H). 13C NMR (CDCl3): δ 152.53,
C
12H20N2Si 220.1396, found 220.1296. Purity was assayed by
1H NMR (see Supporting Information).
2-F or m yl-4-(p yr r olid in -1-yl)-6-(t r im e t h ylsilyl)p yr i-
d in e (1e). tert-Butyllithium (1.7 M in hexanes, 0.31 mL, 0.52
mmol, 1.5 equiv) was added to a -78 °C solution of 2-(tri-
methylsilyl)-4-(pyrrolidin-1-yl)pyridine boron trifluoride com-
plex (0.100 g, 0.35 mmol, 1.0 equiv) in tetrahydrofuran (4 mL).
The solution was allowed to stir for 30 min after which time
N,N-dimethylformamide (43 µL, 0.55 mmol, 1.6 equiv) was
added. The solution was stirred at -78 °C for 1 h and then
allowed to warm to room temperature. Brine and ethyl acetate
were added. The aqueous layer was extracted with ethyl
acetate (1×). The combined organic extracts were dried over
MgSO4 and concentrated under reduced pressure. Purification
by flash chromatography (ethyl acetate) provided 0.039 g (45%)
of 2-formyl-4-(pyrrolidin-1-yl)-6-(trimethylsilyl)pyridine as a
116.93, 115.66, 47.21, 25.17. ΙR 1572.5, 1485.5, 1138.7 cm-1
.
TLC Rf ) 0.41 (5:1 hexanes/ethyl acetate). HRMS (EI) m/z
calcd for C9H10I2N2 399.8934, found 399.8931. Purity was
1
assayed by H NMR (see Supporting Information).
2-Iod o-4,6-(p yr r olid in -1-yl)p yr id in e. A solution of 2,6-
diiodo-4-(pyrrolidin-1-yl)pyridine (17) (0.107 g, 0.27 mmol) in
pyrrolidine (10 mL) was heated to reflux for 6 h after which
time no starting material remained by TLC. The solution was
cooled to room temperature and pyrrolidine was removed
under reduced pressure. The residue was taken up in meth-
ylene chloride and washed with 1 M NaOH (2×), dried over
MgSO4, and concentrated under reduced pressure. Purification
by flash chromatography (9:1 hexanes/ethyl acetate) provided
1
light yellow solid. H NMR (CDCl3): δ 10.02 (s, 1H), 6.95 (d,
J ) 2.7 Hz, 1H), 6.73 (d, J ) 2.7 Hz, 1H), 3.34 (m, 4H), 2.02
(m, 4H), 0.31 (s, 9H). 13C NMR (CDCl3): δ 196.19, 167.72,
153.40, 150.64, 115.40, 103.47, 47.06, 25.31, -1.75. ΙR 1702.8,
1598.3, 1238.1, 836.3 cm-1. TLC Rf ) 0.59 (ethyl acetate).
HRMS (EI) m/z calcd for C13H20N2OSi 248.1345, found 248.1323.
Purity was assayed by 1H NMR (see Supporting Information).
0.080 g of 2-iodo-4,6-(pyrrolidin-1-yl)pyridine (87%) as
a

4664 J . Org. Chem., Vol. 64, No. 13, 1999
Sammakia and Hurley
Ack n ow led gm en t. We thank the National Insti-
tutes of Health (GM48498), Novartis Pharmaceuticals
Corporation, and Pfizer for financial support of this
research. T.S. is a recipient of an American Cancer
Society J unior Faculty Research Award and is an Alfred
P. Sloan Research Fellow. T.B.H. is a recipient of an
American Chemical Society Division of Organic Chem-
istry Fellowship sponsored by Eli Lilly and Company.
We thank Dr. Martin Berliner for assistance with NMR
experiments and helpful discussions, and the referees
for useful comments.
Su p p or tin g In for m a tion Ava ila ble: Selected 1H NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O982281N